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1.
ACS Chem Biol ; 15(4): 1104-1114, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32223208

RESUMO

An automated, high-capacity, and high-throughput procedure for the rapid isolation and identification of biologically active natural products from a prefractionated library is presented. The semipreparative HPLC method uses 1 mg of the primary hit fraction and produces 22 subfractions in an assay-ready format. Following screening, all active fractions are analyzed by NMR, LCMS, and FTIR, and the active principle structural classes are elucidated. In the proof-of-concept study, we show the processes involved in generating the subfractions, the throughput of the structural elucidation work, as well as the ability to rapidly isolate and identify new and biologically active natural products. Overall, the rapid second-stage purification conserves extract mass, requires much less chemist time, and introduces knowledge of structure early in the isolation workflow.


Assuntos
Antineoplásicos/análise , Produtos Biológicos/análise , Ensaios de Triagem em Larga Escala/métodos , Bibliotecas de Moléculas Pequenas/análise , Animais , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Descoberta de Drogas , Gastrópodes/química , Haliclona/química , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , National Cancer Institute (U.S.) , Estudo de Prova de Conceito , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Bibliotecas de Moléculas Pequenas/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Estados Unidos
2.
ACS Chem Biol ; 13(9): 2484-2497, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-29812901

RESUMO

The US National Cancer Institute's (NCI) Natural Product Repository is one of the world's largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine, and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. To address these limitations, the NCI Program for Natural Product Discovery (NPNPD), a newly launched, national program to advance natural product discovery technologies and facilitate the discovery of structurally defined, validated lead molecules ready for translation will create a prefractionated library from over 125,000 natural product extracts with the aim of producing a publicly-accessible, HTS-amenable library of >1,000,000 fractions. This library, representing perhaps the largest accumulation of natural-product based fractions in the world, will be made available free of charge in 384-well plates for screening against all disease states in an effort to reinvigorate natural product-based drug discovery.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Descoberta de Drogas/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Ensaios de Triagem em Larga Escala/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Produtos Biológicos/química , Humanos , National Cancer Institute (U.S.) , Estados Unidos , Fluxo de Trabalho
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